Process for preparing thiazole derivatives

ABSTRACT

PROCESS FOR PREPARING THIAZOLECARBONYLAMINO-SUBSTITUTED BUTENOIC ACIDS AND NEW THIAZOLECARBONYLAMINO-SUBSTITUTED OXAZOLONE COMPOUNDS, E.G., 2 - (N-(2-PHENOXYMETHYL-4THIAZOLYL)CARBONYL)AMINO-3-METHYL-BUTENOIC ACID, AND 2(2&#39;&#39; - PHENOXYMETHYL-4&#39;&#39;-THIAZOLYL)-4-ISOPROPYLIDENE-5-OXAZOLONE BY TREATING A 2-(2-SUBSTITUTED-AMIDO-1-THIOACETYL-2ETHENYL)-4-ISOPROPYLIDENE-5-OXAZOLONE WITH ACID OR BASE, IN AN INERT ORGANIC SOLVENT, OR IN ADMIXTURE WITH THE ALCOHOL OF THE DESIRED ESTER, WHICH PRODUCTS OF THE PROCESS CAN BE USED AS ANTIBIOTICS AND ANTI-FUNGAL AGENTS, AS INTERMEDIATES IN THE SYNTHESIS OF PENICILLIN AND CEPHALOSPORIN COMPOUNDS AND AS ANTIRADIATION CHEMICALS.

United States Patent 3,758,488 PROCESS FOR PREPARING THIAZOLEDERIVATIVES Stephan P. Kukolja and Robert B. Morin, Indianapolis, Indassignors to Eli Lilly and Company, Indianapolis,

No Drawing. Original application May 16, 1969, Ser. No. 825,401, nowPatent No. 3,702,328. Divided and this application July 1, 1971, Ser.No. 159,024

Int. Cl. C07d 91/32, 99/10 US. Cl. 260302 R Claims ABSTRACT OF THEDISCLOSURE CROSS REFERENCE This application is a division of applicationSer. No. 825,401, filed May 16, 1969, now US. Pat. No. 3,702,328.

BACKGROUND OF THE INVENTION Morin and Jackson US. Pat. 3,275,626discloses that penicillin sulfoxides can be rearranged with heat to amixture of products, among which products are thedesacetoxycephalosporins, which lead to valuable antibiotic substances.Since that time, workers in the penicillin and cephalosporin chemicalarts have been studying the effects of various physical and chemicalconditions on penicillin degradation products. Recently, new productswhich have been made by reacting or degrading penicillin sulfoxides withvarious reactants such as trialkyl phosphites and triarylphosphines,followed by reaction with trifluoroacetic acid or sodium acetate are thethiazole acids and esters of the formula where R can be hydrogen, ahydrocarbon group, or a phenoxymethyl, phenylmercapto, or other groupderived from the penicillin used to prepare such compounds, and R ishydrogen, or the residue of ester used in the starting materials. Theselatter compounds have stimulated eflForts to find alternative processesof preparing such compounds.

It is an object of this invention to provide an alternative process forpreparing the thiazolecarbonyl amino-butenoic acids and esters thereof.

It is a further object of this invention to provide some newthiazole-oxazolone compounds, which can be made in the course of theprocess of this invention.

Other objects, aspects, and advantages of the invention will becomeapparent from reading the specification and claims which follow.

Patented Sept. 11, 1973 "Ice THE INVENTION According to this invention,we have discovered a process for preparing compounds having a formulaselected from the group consisting of wherein R is hydrogen, ahydrocarbon radical, preferably having not more than about 12 carbonatoms, phenoxymethyl, phenylmercaptomethyl, or a similar group derivedfrom a penicillin starting material, and R is hydrogen, or the estergroup of an alcohol present in the reaction mixture, which processcomprises treating with acid or base in an inert organic solvent, ormixed with a desired alcohol, or an aqueous medium, an oxazolonecompound of the formula wherein R is as defined above, to form an acidor ester of Formula a, above, in admixture with the oxazolone compoundof Formula b, or with aqueous base to form the compound of Formula a asthe acid (R' being hydrogen).

The starting material of Formula 0 above can be prepared as one ofseveral products obtained by the reaction of penicillin V with aceticanhydride at 120-130 C. for minutes. The reaction of penicillin G withacetic anhydude was reported in the penicillin monograph. The Chemistryof Penicillin, The Princeton Press (1949) p. 168, and the appearance ofthe absorption maximum at 320 m was noticed. However, these compoundswere neither contemplated, identified, or isolated. From our work, wenow believe that a compound of Formula c was formed. The startingmaterial (c) is isolated from the mixture by chromatography over silicagel by known procedures.

In conducting the process of this invention using the acidic procedures,the oxazolone starting material of Formula c is dissolved in an inertorganic solvent such as methylene chloride, chloroform, benzene,heptane, toluene, or the like and saturated with hydrogen chloride gas,with hydrogen bromide, or mixed with an acid such as sulfuric acid,p-toluenesulfonic acid, or other nonoxidizing acid, and is allowed tostand or is agitated for from about one hour to 24 hours, at 0 to 50 C.,preferably at room temperature to form the compound of Formula a, mixedwith compound of Formula b. Compounds of Formula a generally precipitatefirst from the solution and can usually be separated from the reactionmixture by filtration procedures, and purified by recrystallization fromorganic solvents, e.g., ethanol, ethyl acetate, and the like, by knownprocedures. Compounds of Formula b are generally recovered byevaporating the solvent from the reaction mixture after the precipitatecontaining compound of Formula a has been separated, and redissolvingthe residue in an appropriate solvent such as ethanol, ethyl acetate,acetone, and the like for recrystallization therefrom. Mixedre-crystallization solvent systems such as ethanol/acetone,acetone/ethyl acetate, nitrornethane/ethyl acetate and the like can beused to effect purification.

The thiazole-containing butenoic acid compounds of Formula a can also beobtained by treating the oxazolone starting material with a base,preferably an aqueous alkali metal hydroxide solution, e.g., sodiumhydroxide, potassium hydroxide, or with a trialkylamine such astrimethylamine, tributylamine, pyridine, or the like.

In conducting the process of this invention to make esters of Formula aabove, wherein R is the ester group, the oxazolone starting material(c), as such or in solution, is mixed with an acidified alcohol mixture.The alcohol is that desired for the ester in the product (a) and is onewhich is liquid at the reaction temperature. The acid condition can besatisfied by any non-oxidizing acid but is preferably obtained by theuse of hydrogen chloride, hydrogen bromide, sulfuric acid,p-toluene-sulfonic acid, methanesulfonic acid, or the like dissolved inthe alcohol. Examples of alcohols which can be used to form the esterproducts are the C to C -alkanols such as methanol, ethanol,isopropanol, tert-butanol, hexanol, and other alcohols known to produceeasily cleavable esters of penicillin and cephalosporin compounds.Examples of such other alcohols which can be used to produce easilycleaved esters include 2,2,2-trichloroethanol, benzyl alcohol,p-nitrobenzyl alcohol, C to C -tert-alkenyl alcohols such astert-butenyl alcohol, tert-heptenyl alcohol, tert-alkynyl alcohols suchas tert-pentynyl alcohol and tert-heptynyl alcohol, as well astrimethylsilyl alcohol, or the like. In some cases, chlorides orbromides may be used in place of the alcohol in this process to form thedesired ester. For example, in place of the various benzyl alcoholswhich can be used, the corresponding benzyl chloride or bromide can beused in place of the alcohol in alkaline media, e.g., p-nitrobenzylbromide, pmethoxybenzyl chloride, benzyl bromide, and the like.

In the starting materials (c) and in the products of the process (a) and(b), R can be hydrogen, a C to C -hydrocarbon radical, or the residue ofthe acyl group in the 6-position of a penicillin excluding the CO'group. Hence, R can be exemplified by C to C -a1kyl radicals such asmethyl, ethyl, propyl, isopropyl, n-butyl-tert-butyl, heptyl, octyl,dodecyl, C to C -a1kenyl radicals such as propenyl, ethyl, butenyl,octenyl, undecenyl, C to C alkynyl, e.g.. ethynyl, propynyl, hexynyl,and the like, cycloalkyl, and cycloalkenyl radicals such as cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopentenyl,cyclohexenyl, and aromatic hydrocarbon groups such as phenyl, tolyl,phenylmethyl, phenylethyl, phenylpropyl. R can also be a wide variety ofsubstituents common to the presently known penicillins. As a practicalmatter, R is generally hydrogen, or the hydrocarbon, hydrocarbonOCHhydrocarbonSCH group from one of the commercially available penicillinsproduced on a scale. Thus, 'R is preferably phenoxymethyl frompenicillin V (phenoxymethylpenicillin) phenylmethyl from penicillin G(phenylmethylpenicillin) phenylmercaptomethyl fromphenylmercaptomethylpenicillin, as a C -C -a1kyl group from one of the C-C alkylpenicillins, and penicillins of these types substituted withnon-interfering substituents such as chlorine, hydroxy groups, aminogroups, and the like. Such a variety of R groups can be furtherexemplified by and obtained by the semi-synthetic precursor penicillinfermentation processes disclosed, e.g., in Behrens U.S. Pats. 2,479,295to 2,479,297, 2,562,407 to 2,562,411, and 2,623,876.

The products of this invention can be used as antiradiation chemicals,generally as set forth in Radiation Research, 1, pp. 13-2l (1957). Theycan be used as intermediates in the synthesis of known and new fl-lactamantibiotics. For this latter utility, the compounds of Formula a or bare subjected to photoisomerization conditions, e.g., as describedgenerally in J. Am. Chem. Soc.,

4 90, p. 2333 (1968) to form the [t-lactam compounds, followed bytreatment with a peracid oxidizing agent to form a mixture of adesacetoxycephalosporin sulfoxide and a 2hydroxymethylpenicillinsulfoxide having the formulas wherein R and R are as defined above. Thedesacetoxycephalosporin sulfoxide compound can be separated from theZ-hydroxymethylpenicillin compound by known procedures and reduced tothe desacetoxycephalosporin compounds by procedures now known, e.g.,with sodium dithionite in acetyl chloride. Then the 7-acyl group can becleaved by known procedures, for example, by treatment with PClg andpyridine, followed by treatment with methanol, and then with water toform the 7-aminodesacetoxycephalosporanic acid (7-ADCA) or an esterthereof. The 7-ADCA acid or ester can then be treated with a variety ofacylating agents. For example, a mixed anhydride form of Da-phenylglycine in which the amino group of the glycine is protected,e.g. with tert-butoxycarbonyl or benzyloxycarbonyl can be reacted withthe 7- ADCA or ester thereof, followed by removal of the aminoprotecting group and any ester group by known procedures to obtaincephalexin, a known orally absorbed antibiotic.

The thiazole acid and ester compounds are useful as antibiotics. Forexample, the compound 3-methyl-2-(2'- phenoxymethyl)4-thiazolylcarboxarnido) butenoic acid, a compound of Formula a above,is active as an antibiotic against the bacterial organism, Pseudomonassolanacearum, strain 815 at a concentration of micrograms/ ml. asdetermined by an agar dilution test method, described by Steers andPoltz in Antibiotics and Chemotherapy, 9, p. 307 (1959). As anotherexample, the ester, methyl N-(2'-phenoxy methyl-4-thiazolylcarbonyl)2-amino-3-methylbutenoate is active against the fungus Botrytis cinerea ata concentration of 100 micrograms per milliliter in a similar agardilution test. These compounds can be compounded into ointment andlotion compositions by known methods and applied to surface cuts andabrasions to prevent infections by Pseudomonas type organisms. The newthiazole-oxazolone compounds of Formula b are more important for theiruse as intermediates for the preparation of compounds of Formula a byacid hydrolysis thereof.

Additional compounds which can be prepared by the acidic or basichydrolysis procedures of this invention are exemplified by thefollowing:

N-(4 thiazolylcarbonyl) 2 amino-3-methyl-2-butenoic acid and2-(4'-thiazolyl)-4-isopropylidene-5-oxazolone from2-(2-formamido-1'-thioacetyl-2'-ethenyl)4-isopropylidene-S-oxazolone inmethylene chloride saturated with hydrogen chloride;

N (2 heptyl-4-thiazolylcarbonyl)2-amino-3-methyl- Z-butenoic acid and2-(2'-heptyl-4-thiazoly1)-4isopropylidene-S-oxazolone from2-(2'-heptanoylamido-l-thioacetyl- Z-ethenyl) 4isopropylidene-S-oxazolone and hydrogen bromide in benzene;

N (2' phenylmercaptomethyl 4'thiazolylcarbonyl)2-amino-3methyl-2-butenoic acid and2-(2-phenylmercaptomethyl-4-thiozolyl)4-isopropylidene 5 oxazolone from2-(2'-pheny1mercaptoacetamido-1'-thioacetyl-2-ethenyl)4-isopropylidene-S-oxazolone and p-toluenesulfonic acid inheptane;

Tert-butyl N (2' phenylmethyl-4'-thiazolylcarbonyl)- 2 amino 3methyl-Z-butenoate and tert-butyl 2-(2- phenylmethyl 4' thiazolyl) 4isopropylidene-S-oxazolone from 2 (2' phenylacetamido-1'-thioacetyl-2-ethenyl)-4-isopropylidene-5-oxazolone and hydrogen chloride intert-butanol;

N (2' methyl 4' thiazolylcarbonyl)-2-amino-3- methyl 2 butenoic acidfrom 2-(2'-acetamido-1'-thioacetyl 2'ethenyl)-4-isopropylidene-5-oxazolone and aqueous potassium hydroxide;and

Tert-pentynyl N-(2' phenoxymethyl 4' thiazolylcarbonyl) 2 amino 3methyl-2-butenoate and tertpentynyl 2 (2' phenoxymethyl 4'thiazolyl)-4-isopropylidene-S-oxazolone from 2-(2'-phenoxyacetamido-1'-thioacetyl 2' ethenyl)-4-isopropylidene-5-oxazolone and hydrogenchloride in tert-pentynyl alcohol.

The invention is also illustrated by the following detailed examples ofthe preparation of the new compounds of invention, but we do not intendthat these examples limit the invention of these compounds.

EXAMPLE 1 (A) Starting material2-(2-phenoxyacetamido-l-thioacetyl-2-ethenyl-)isopropylidene-5-oxazolone A mixture of g. of penicillin V in 200 ml. ofan anhydride was heated at 120130 C. for 45 minutes under a heliumatmosphere and then evaporated to dryness at reduced pressure. The darkoily residue obtained thereby was taken up in benzene andchromatographed through a silica gel (200 g.) column, using a mixture ofbenzene and ethyl acetate as the eluting solvent. The eluate wascollected in 21 ml. fractions at 21 minute intervals, which wereanalyzed by thin layer chromatography and suitably combined for productisolation.

Fractions 43-82 were collected and evaporated. The residue was treatedwith ethyl ether, left in a refrigerator overnight, and 1.31 g. ofcrystals, M.P. 157-166 C-, were collected. It was recrystallized fromacetone (1 g. from 38 ml.) and nice, colorless crystals, melted at 17274C.; A max. (EtOH) 320 mu (6 28,800) were obtained.

Analysis.-Calcd. for C H N O S (percent): C, 57.74; H, 4.84; N, 7.48; S,8.57. Found (percent): C, 57.71; H, 4.79; N, 7.35; S, 8.72.

N (2 phenoxymethyl-4-thiazolecarbonyl)-2-amino-3- methyl 2 butenoic acidand 2-(2-phenoxymethyl-4- thiazolyl- -4-isopropylidene-5-oxazolone Asolution of 1.0 g. of2-(2-phenoxyacetamido-l-thioacetyl-2-ethenyl-)-4-isopropylidene-S-oxazolonein 40 ml. of methylene chloride was saturated with HCl gas and left atroom temperature for 16 hours. The precipitated product was filtered anddried, giving 520 mg. of crystals. It was recrystallized from ethanoland nice, colorless crystals of thiazole acid, M.P. 178.5179 C., wereobtained.

Analysis.-Calcd. for C H N O S (percent): C, 57.83; H, 4.85; N, 8.43; S,9.65. Found (percent): C, 57.88; H, 4.79; N, 8.45; S, 9.67.

The filtrate (after 520 mg.) was evaporated to dryness and the residuerecrystallized from ethanol, giving 320 mg. of colorless crystals, M.P.13334 C. After recrystallizations from a mixture of ethanol and acetone,the thiazole-oxazolone melted at 135-36 C.

Analysis.--Calcd. for C H N O S (percent): C, 61.14; H, 4.49; N, 8.91;S, 10.20. Found (percent): C, 60.87; H, 4.63; N, 8.94; S, 10.43.

EXAMPLE 2 N- (2-methyl-4-thiazolecarbonyl) -2-amino-3-methyl-2- butenoicacid To a solution of 564 mg. of 2-(2-phenoxyacetamido-1 thioacetyl 2ethenyl-)-4-isopropylidene-5-oxazolone in 100 ml. of acetone 3 ml. of asolution of 2 normal sodium hydroxide was added and stirred at roomtemperature for 2 hours. The solvent was evaporated at a reducedpressure,

the residue triturated with ethyl ether, and then dissolved in 60 ml. of0.2 N hydrochloric acid. The solution was extracted with ethyl acetate,the extract washed with water, dried and the solvent evaporated to givean oil which was triturated with petroleum ether. The residue (490 mg.)was shaken on an ultrasonic vibrator with 12 ml. of water and theinsoluble part filtered and washed with water, giving 150 mg. ofN-(2-phenoxymethylt thiazolecarbonyl)-2-amino-3-methyl-2-butenoic acid.

The filtrate was evaporated at reduced pressure and the residue (220mg.) triturated with ether. Insoluble material melted at 192-94 C. Itwas recrystallized from ethanol and nice crystals ofN-(2-methyl-4-thiazolecarbonyl)- 2-amino-3-methyl-2-butenoic acid meltedat 198-99" C. Mass spectrum showed molecular ion at m./e. 240.

Analysis.Calod. for C H N O S (percent): C, 49.9; H, 5.04; N, 11.66; S,13.35. Found (percent): C, 49.05; H, 5.26; N, 11.13; S, 13.05.

EXAMPLE 3 Methyl N-(2-phenoxymethylthiazole-4-carbonyl)-2-amino-3-methylbutenoate A 3.0 g. portion of2-(2'-phenoxyacetamido)-1-thioacetyl 2'ethenyl)-4-isopropylidene-5-oxazolone was added to 50 ml. of methanolwhich had been previously saturated with hydrogen chloride and stirredat room temperature for 20 hours. The solvent was evaporated, and theresidue was dissolved in ml. of chloroform. The resulting solution waswashed twice with a 5 percent solution of sodium bicarbonate. Theorganic layer was separated and dried. The solvent was evaporated andthe residue was recrystallized from 12 ml. of ethanol, giving 1.65 g. ofthe title ester, M.P. 136 C.

Analysis.Calcd. for C H N O S (percent): C, 58.94; H, 5.23; N, 8.08; S,9.25. Found (percent): C, 58.73; H, 5.19; 'N, 8.00; S, 9.37.

We claim: 1. A process for preparing a compound of the formula whichcomprises reacting an oxazolone compound of the formula with an acid ora base in the presence of an inert organic liquid, an alcohol, or anaqueous medium, in which, in the above formulae, R is hydrogen, ahydrocarbon group having from 1 to 12 carbon atoms, phenoxymethyl, orphenylmercaptomethyl, and R is hydrogen or the ester residue of analcohol present in the reaction mixture.

2. A process as defined in claim 1 wherein an inert organic solventsaturated with hydrogen chloride is mixed with an oxazolone wherein R isphenoxymethyl to form a compound wherein R is phenoxymethyl, and R ishydrogen.

3. A process as defined in claim 1 wherein an aqueous alkali metalhydroxide solution is mixed with an oxazolone wherein R is phenoxymethylto form a compound wherein R is phenoxymethyl and R is hydrogen.

4. A process as defined in claim 1 wherein an alcohol 7 8 saturated withhydrogen chloride is mixed with an ox- References Cited azolone whereinR is phenoxymethyl to form a compound UNITED STATES PATENTS wherein R isphenoxymethyl, and R is the ester residue of the alcohol present in thereaction mixture. 3,5943 89 7/1971 Cooper 260-302 R 5. A process asdefined in claim 4 wherein methanol 5 RICHARD J GALLAGHER PrimaryExaminer saturated with hydrogen chloride is mixed with2-(2'-phenoxy-acetamido '1 thioacetyl 2 ethenyl)-4-isopropyl- U S C1 X Ridene 5 oxazolone to form methylN-(2-phenoxymethy1thiazoly1-4-carbonyl)-2-amino-3-methylbutenoate.260-302 H

